Studies completed under our previous grants have documented various behavioral components, electrophysiological correlates, and the natural history of the chronic stimulant intoxication syndrome in three species; i.e., the rat, cat, and monkey. The syndrome develops in four phases: 1) initial; 2) major ontological phase; 3) establishment of end-stage behaviors; and 4) long term, post-drug residua. Each stage is distinct and responds to differential manipulation. The end-stage and residua syndromes, we hypothesize and have partially documented, are resolutions derived from several interaction factors: 1) initial prepotent behaviors including learned and species-specific acts; 2) reinforcement mechanisms interacting with prepotent behaviors; 3) establishment of hyperactive gradients of neural activity; 4) dennervation supersensitivity through regional neurotransmitter depletion and/or neuronal damage, 5) change in the balance of CNS neurotransmitter effects, 6) loss of mechanisms integrating arousal level and basic postural-attitudinal sets, and 7) lowered thresholds for preseizure and seizure electrophysiological activity perhaps through a kindling mechanism. The goal of the proposed research is to delineate further these mechanisms at each stage by 1) use of systemic or cannula application of pertinent neurotransmitter agonists and antagonists to identify the neural transmitters mediating these behaviors; 2) use of the chronic model to identify the conditioned aspects of each stage; 3) use of rat startle reaction as a model for the hyperreactive, end-stage behavior; 4) testing the kindling mechanism hypothesis of reverse tolerance to cocaine; 5) manipulating the topography of the drug self-administration operant response and assessing its effect on drug intake characteristics, and 6) evaluating the electrophysiological and behavioral reinforcement patterns associated with drug reinforcement.